12-132668431-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006231.4(POLE):​c.2098C>G​(p.Pro700Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P700L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

POLE
NM_006231.4 missense

Scores

2
3
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.79
Variant links:
Genes affected
POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17183247).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POLENM_006231.4 linkuse as main transcriptc.2098C>G p.Pro700Ala missense_variant 19/49 ENST00000320574.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.2098C>G p.Pro700Ala missense_variant 19/491 NM_006231.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T;.
Eigen
Benign
-0.059
Eigen_PC
Benign
0.0019
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.0038
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.43
T
PROVEAN
Pathogenic
-6.4
D;D
REVEL
Benign
0.18
Sift
Benign
0.077
T;T
Sift4G
Benign
0.13
T;T
Polyphen
0.026
B;B
Vest4
0.21
MutPred
0.38
Gain of catalytic residue at P696 (P = 0.001);.;
MVP
0.40
MPC
0.24
ClinPred
0.80
D
GERP RS
4.0
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.2
Varity_R
0.22
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-133245017; API